The Updated Treatment Algorithm for Bladder Cancer
Key Points
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In non–muscle-invasive bladder cancer (NMIBC), the addition of immunotherapy to the historical standard of single-agent Bacillus Calmette-Guérin (BCG) has improved outcomes.
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Enfortumab vedotin (EV) plus pembrolizumab is set to become the new standard of care neoadjuvant and adjuvant regimen for patients with muscle-invasive bladder cancer (MIBC), regardless of cisplatin eligibility.
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The treatment algorithm for advanced or metastatic bladder cancer is shifting due to the updates in earlier treatment settings, although targeted therapy options are expanding.
Treatment Algorithms for Bladder Cancer
Cohosts of the Oncology Brothers podcast, Rahul Gosain, MD, MBA, of Wilmot Cancer Institute, and Rohit Gosain, MD, of Roswell Park Comprehensive Cancer Center, met with Stephanie Berg, DO, a medical oncologist from Dana-Farber Cancer Institute, and Joshua Meeks, MD, PhD, a urologist from Northwestern University, to unpack the treatment algorithm for bladder cancer populations. The doctors discussed the standards of care and reviewed recent practice-changing trials.
Standard of Care Treatments for NMIBC
Historically, medical oncologists have had a limited role in NMIBC, and urologists have led treatment. For many years, single-agent BCG has been the standard of care for NMIBC. Recently, the CREST and POTOMAC trials sought to improve BCG outcomes by combining treatment with PD-(L)1–targeted immunotherapy agents. POTOMAC evaluated BCG plus 1 year of intravenous durvalumab, while CREST evaluated BCG plus 2 years of subcutaneous sasanlimab. Both trials were positive, supporting that BCG plus maintenance immunotherapy can cure more patients with NMIBC.
While CREST and POTOMAC met their event-free survival and disease-free survival endpoints, respectively, neither trial has mature long-term overall survival (OS) data. Without more robust data, it’s unclear which patients with NMIBC should be selected for additional durvalumab or sasanlimab, as immune-related toxicities can be meaningful. Potentially, these combinations may strike a middle ground between radical cystectomy and single-agent BCG for patients with high-risk disease features who need more potent efficacy but want to avoid surgery, Dr. Meeks suggested.
Surgery–Eligible MIBC
The doctors then discussed the treatment algorithm for patients with MIBC. Historically, this group of patients has been subdivided into those eligible for surgery and those eligible for cisplatin–based chemotherapy. However, several trials have recently shifted the treatment paradigm with immunotherapy–based combinations.
The NIAGARA trial showed that adding perioperative durvalumab to the historical standard of neoadjuvant gemcitabine plus cisplatin improved OS in patients with MIBC, and the FDA approved this regimen on March 28, 2025. Subsequently, the KEYNOTE-905/EV-303 trial established that perioperative EV plus pembrolizumab improved outcomes compared with immediate cystectomy for cisplatin–ineligible patients with MIBC. The FDA approved this regimen on November 21, 2025. Most recently, the KEYNOTE-B15/EV-304 trial reported that EV plus pembrolizumab also improved outcomes compared with neoadjuvant gemcitabine plus cisplatin. Given the combined data for EV plus pembrolizumab, it is likely to become the new standard of care for patients with MIBC regardless of cisplatin eligibility.
While the NIAGARA and KEYNOTE trials are practice-changing, it’s still unclear how necessary the adjuvant immunotherapy component is, particularly if patients achieve a pathological complete response (pCR) after neoadjuvant therapy and surgery. The VOLGA trial is investigating neoadjuvant combinations of durvalumab, EV, and tremelimumab followed by surgery and adjuvant durvalumab with or without 1 cycle of tremelimumab. These data may help elucidate the role of adjuvant therapy, said Dr. Berg.
Surgery–Ineligible MIBC
The standard of care for patients with MIBC ineligible for surgery is typically concurrent chemoradiation, often with cisplatin–based chemotherapy. While the immunotherapy–based regimens from the NIAGARA and the KEYNOTE trials were studied and approved in surgery–eligible patients, they may still be viable in ineligible patients. Patients who decline or are not fit enough for surgery may receive neoadjuvant EV plus pembrolizumab, followed by consolidation chemoradiation if they are fit enough, suggested Dr. Berg. Generally, patients avoiding radical cystectomy should receive as much adjuvant therapy as possible or as tolerated, said Dr. Meeks.
Advanced or Metastatic Bladder Cancer
The treatment algorithm for advanced or metastatic bladder cancer can differ between patients with relapsed or refractory disease after prior systemic therapy versus patients diagnosed with de novo metastatic disease. For de novo metastatic patients, immunotherapy–based combinations like EV plus pembrolizumab or nivolumab plus gemcitabine and cisplatin are approved upfront treatment options.
For patients with relapsed or refractory disease, the upfront treatment options have shifted due to the expansion of EV plus pembrolizumab to the neoadjuvant and adjuvant setting. Instead of rechallenging with immunotherapy, physicians can consider erdafitinib for patients with FGFR3 alterations or trastuzumab deruxtecan for patients with HER2–positive disease. If targeted therapies are not applicable, platinum-based chemotherapy may be the next best option, said Dr. Berg.
Generally, this is a difficult population to treat, and oncologists should consider clinical trials for eligible patients. Many recent urothelial cancer trials have expanded their inclusion criteria to include less fit patients, Dr. Berg said. Dr. Berg’s center is enrolling patients for a phase I/II trial investigating EV plus pembrolizumab plus sacituzumab govitecan, another antibody drug conjugate.